H3 relaxin inhibits the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose

Abstract

Excessive production of reactive oxygen species (ROS) and P2X7R activation induced by high glucose increases NLRP3 inflammasome activation, which contributes to the pathogenesis of diabetic cardiomyopathy. Although H3 relaxin has been shown to inhibit cardiac fibrosis induced by isoproterenol, the mechanism has not been well studied. Here, we demonstrated that high glucose (HG) induced the collagen synthesis by activation of the NLRP3 inflammasome, leading to caspase‐1 activation, interleukin‐1β (IL‐1β) and IL‐18 secretion in neonatal rat cardiac fibroblasts. Moreover, we used a high‐glucose model with neonatal rat cardiac fibroblasts and showed that the activation of ROS and P2X7R was augmented and that ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation was critical for the collagen synthesis. Inhibition of ROS and P2X7R decreased NLRP3 inflammasome‐mediated collagen synthesis, similar to the effects of H3 relaxin. Furthermore, H3 relaxin reduced the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in response to HG. These results provide a mechanism by which H3 relaxin alleviates NLRP3 inflammasome‐mediated collagen synthesis through the inhibition of ROS and P2X7R under HG conditions and suggest that H3 relaxin represents a potential drug for alleviating cardiac fibrosis in diabetic cardiomyopathy.

Gypenosides improve diabetic cardiomyopathy by inhibiting ROS‐mediated NLRP3 inflammasome activation

“…Inhibiting TXNIP can effectively down‐regulate NLRP3 inflammasome activation and IL‐1β secretion . Moreover, one study has recently shown that ROS can directly induce the formation of the caspase‐1‐ASC complex and activate the NLRP3 inflammasome . In the current study, we found that ROS could induce cytochrome c influx into cytoplasm, which directly bound to NLRP3 and led to NLRP3 inflammasome activation.…”

“…Recent studies suggest that mitochondrial ROS is required for NLRP3 inflammasome activation . Moreover, many studies have indicated that mitochondrial damage and oxidative stress are important risk factors for DCM and that mitochondrial ROS is a pivotal link between oxidative stress and NLRP3 inflammasome activation . Recently, a study has shown that monocytes and/or MDMs from T2D or DCM patients stimulated with DAMP release an elevated level of ROS .…”

Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways

“…Therefore, there is considerable in vitro and in vivo evidence that relaxin is an important factor in the progression and treatment of fibrosis. In addition, there is emerging evidence that additional relaxin family peptides, such as relaxin-3, may also play a role in fibrosis (Hossain et al, 2011;Zhang et al, 2018).…”

Coriolus versicolor alleviates diabetic cardiomyopathy by inhibiting cardiac fibrosis and NLRP3 inflammasome activation

“…Cl.casp‐1 leads to mature IL‐1β and IL‐18 release, which triggers inflammation. In diabetes‐related studies, streptozocin injection increases NLRP3‐induced inflammation; however, NLRP3 inhibition ameliorates cardiac dysfunction in a model of DCM (Luo et al, ; Ye, Bajaj, Yang, Perez‐Polo, & Birnbaum, ; X. Zhang et al, ). All the above studies demonstrated that inhibition of cardiac fibrosis and inflammation at the same time may be a promising therapeutic strategy for DCM.…”